The present invention relates to novel inclusion complexes of a high potent opioid peptide, Tyrosyl-D-alanyl-glycyl-N-methylphenylalanyl-glycyl-isopropylamide with cyclodextrin derivative. More particularly, the invention relates to Tyrosyl-D-alanyl-glycyl-N-methylphenylalanyl-glycyl-isopropylamide with cyclodextrin derivatives such as beta-cyclodextrin, hydroxypropyl-beta cyclodextrin, hydroxyethyl-beta-cyclodextrin, or Dimethyl-beta cyclodextrin. The invention also relates to a process for the preparation of pharmaceutical compositions containing the inclusion complexes of opiod peptide and the use thereof in the treatment of alleviating pain and acute inflammation, which can be used as a substitute- for narcotic analgesics.
There exists a constant need for preparing novel centrally acting agents which can be utilized as substitute for the narcotic analgesics, currently being used, having improved biopharmaceutical properties such as low toxicity, lesser tolerance, longer duration of action and least abuse potential. The development of the peptide as drug is restricted due to its poor oral efficacy. In view of this, it is essential to develop orally active formulations. There has been tremendous emphasis on the development of innovative strategies for the oral delivery of peptide based, drugs, with increased water solubility, dissolution, bioavailability and improved oral efficacy.
Soon after the discovery of enkephalin by Huges et. Al [Huges et. Al, Nature 258, 577 (1975)]. an endogenously occurring pentapeptide with morphinomimetic activity, structure activity relationship studies were undertaken world-wide with the objective of getting a synthetic congener that would be clinically acceptable pain killer as substitute to morphine. Since the analgesia evoked by enkephalins was only weak and transient following their administration by intra-cerebral route, greater emphasis was laid on the structural modification of the penta peptide which would lead to the peptide(s) capable of eliciting profound analgesis even after their systemic administration.
The two best enkephalin analogues that had undergone fairly extensively clinical studies so far, are the Sandoz compound FK-33-824 [Tyr-D-Ala-Gly,-Met(o)-01] and the Lilly compound met-keohamid (Tyr-D-Ala-Gly-Phe-MeMet-NH2). [Von Graffenreid, B., del Pozo, E., Roubicek, J., Krebs, E., Poldinger, W., Burmeister, P. and Kerp, L., Nature, 272, 729 (1978) and, Frederickson, R. C. A., Smithwick, E. L., Shuman, R. and Bernis, K. G., Science, 211, 603, (1981) Frederickson, R. C. A., In xe2x80x9cOpioid Peptides: Molecular Pharmacology, Bio synthesis and analysisxe2x80x9d Rapaka, R. S. and Hawks, R. L. eds. NIDA Research Monograph, 70 367. (1986)] FK-33-824 gave only slight preference for p-receptors and met-kephamid was found essentially non-elective for xcexc and xcex4 receptors. A strong analgesic effect was exerted by both the compounds by systemic route of administration. However, due to a number of serious side effects produced by FK-33-824 therefore it was no longer pursued for further developments as candidate analgesic drug. Relatively fewer side effects were observed with met-kephamid, but due to its hypotensive effect this compound was also finally abandoned.
Another enkephalin analogs Tyr-D-Met-Gly-Phe-Pro-NH2 [Flodes, J., torok, K., Szekeley, J. I., Borvenderg, J., Karezag, I., Tolna, J., Marosfi, S., Varadi, A., Gara. A., Ronai. A. Z. and Szilaggi, G. Life Sciences 33, Supp. 1, 769 (1983)] and Tyr-Arg-Gly-Phe(pNO2)-Pro-NH2 (BW-443C) (SEQ ID NO. 1) [Follenfani, R. I., Hardy, G. W., Lowe, L. A., Schneider, C. and Smith, T. W. Br. J. Pharmacol. 93, 85, (1988) and Kriss, M. G., Gralla, R. J., Clark, R. A., Tyson, L. B. and Groshen, S., J. Clin. Onclol., 6, 663, (1988)] were also shown to be more potent analgesic than morphine but due to number of side effects these compounds were also dropped after initial clinical trials. Similarly, structure activity relationship studies were undertaken in our laboratory and an enkephalin analog Tyr-D-Ala-Gly-MePhe-Gly-NHC3H7 [Raghubir, R., Patnaik, G. K., Sharma, S. D., Mathur, K. B. and Dhawan B. N., In recent progress in chemistry and biology of centrally acting peptides. Dhawan B. N. and Rapaka R. S. eds., .167, (1988) and Indian Patent no. 173568 19.10.1989] synthesized earlier in our laboratory and found to be more potent than morphine following systemic administration. This is a highly xcexc-receptor selective in central and peripheral assay and produces highly profound and long lasting analgesia. (C. Nath, G. K. Patnaik, W. Haq, K. B. Mathur, R. C. Srimal, B. N. Dhawan and F. Porreca, Pharmacological Research, 31, 269-273, 1995) The compound and its process for the synthesis was first disclosed in Indian patent [Indian Patent no. 173568 19.10.1989]. Subsequently chronic and subacute toxicity studies on this compound were carried out and it is now disclosed that this compound is safe and did not produce any noticeable toxic side effects. This compound was also studied for their addiction liabilities and tolerance and found to elicit significantly reduced tolerance and addiction properties as compared to morphine. The compound is virtually devoid of any major CNS effects like sedation and respiratory depression; it is also virtually devoid of any significant cardiovascular effects. Therefore, this compound has .a potential as centrally active analgesic agent, which can be used as a substitute to narcotic analgesics (Morphine and related substances). However, this compound upon oral administration produced poor response and extremely high dose is required to obtain similar magnitude of response as observed after parenteral administration owing to its decomposition and poor absorption. The oral efficacy of the therapeutic agents is considered to be highly desirable, therefore, inspite of a profound analgesia and favourable pharmacological effect and almost devoid of toxic effects, the. development of the peptide as drug is restricted due to its poor oral efficacy. In view of this, it is essential to develop orally active formulations.
There has been. tremendous emphasis on the development of innovative strategies for the oral delivery of peptide based drugs, (A Fasano. (1998) TIBTECH., 16, 152-157) with increased water solubility, dissolution, bioavailability and improved oral efficacy (Z. Shao, 1992). Cyclodextrins are reported in the literature that they increase water solubility, dissolution, bioavailability and stability of compound by forming inclusion complexes. [R. Krishnamoorthy and A. K. Mitra, Pharma. Res., 9: 1157-1163 (1992)]. Recently it was reported in the literature that the xcex2-cyclodextrin inclusion complex increase the half life of Leu-enkephalin from 45 min to 75 min in case of enzyme hydrolysis with leucine amino peptidase (W. J. Erwin., A. K. Dwivedi, P. A. Holbrook, and M. J. Dey, Pharma Res., 11, 1994, 1698-1703). Therefore, the preparation of inclusion complex of peptides and other substances with cyclodextrin are reported in the literature. The advantage of binding substances into inclusion complexes with cyclodextrin is also known in other substances. U.S. Pat. Nos. 4,603,123, 5,840,714 and 5,855,916 disclosed the increased therapeutic efficacy and reduced toxic effects of piroxicam, ibuproxam and acid base type drugs respectively.
The main object of the present invention is to provide novel L-Tyrosyl-D-alanyl-glycyl-N-methylphenylalanyl-glycyl-isopropylamide: cyclodextrin complexes having significantly improved oral efficacy and prolonged duration of acion.
Another object is to provide novel inclusion complexes that can be utilised as substitute for narcotic analgesics, said complexes having improved biopharmaceutical properties such as low toxicity, lesser tolerance, longer duration of action and least abuse potential.
Still another object is to provide novel L-Tyrosyl-D-alanyl-glycyl-N-iniethylphenylalanyl-glycyl-isopropylamide complexes with increased water solubility, dissolution , bioavailability and improved oral/transdermal efficacy.
Yet another object is to provide pharmaceutical compositions containing said novel inclusion complexes having improved analgesic activity with longer duration of activity and improved efficacy.
Still another object is to provide methods for the treatment of acute inflamnmatory conditions employing the said inclusion complexes.
The above and other objects are realized by the present invention that provides novel inclusion complexes having improved analgesic prope and longer duration of activity. The invention also provides pharmaceutical compositions containing said inclusion complexes and methods of treatment employing such inclusion complexes.